aLaboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;bDanish Aging Research Center, Department of Molecular Biology and Genetics, University of Aarhus, 8000 Aarhus C, Denmark;

cLaboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;gDepartment of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

aLaboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;hDanish Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark

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Significance

Alzheimer’s disease (AD) is the most common form of dementia, and there is no cure. DNA repair activity is deficient in AD patient brains, especially DNA polymerase β (Polβ), a key protein in DNA base excision. NAD+ is a cellular metabolite critical for mitochondrial health and biogenesis, stem cell self-renewal, and neuronal stress resistance. This study shows that NAD+ levels were decreased in a new AD mouse model with introduced DNA repair deficiency (3xTgAD/Polβ+/−), and NAD+ supplementation with nicotinamide riboside significantly normalized neuroinflammation, synaptic transmission, phosphorylated Tau, and DNA damage as well as improved learning and memory and motor function. This has implications for human AD intervention.

Abstract

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ+/− mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ+/− mice have a reduced cerebral NAD+/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ+/− mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ+/− mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ+/− mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ+/− mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have therapeutic potential for AD.

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